PUBLICATION
Triphenyl phosphate-induced developmental toxicity in zebrafish: Potential role of the retinoic acid receptor
- Authors
- Isales, G.M., Hipszer, R.A., Raftery, T.D., Chen, A., Stapleton, H.M., Volz, D.C.
- ID
- ZDB-PUB-150301-2
- Date
- 2015
- Source
- Aquatic toxicology (Amsterdam, Netherlands) 161C: 221-230 (Journal)
- Registered Authors
- Keywords
- Flame retardant, Retinoic acid receptor, Triphenyl phosphate, Zebrafish
- MeSH Terms
-
- Animals
- CHO Cells
- Cricetinae
- Cricetulus
- Cytochrome P-450 Enzyme System/genetics
- Drug Synergism
- Embryo, Nonmammalian/drug effects
- Embryonic Development/drug effects
- Gene Expression Regulation/drug effects
- Humans
- Organophosphates/toxicity*
- Receptors, Retinoic Acid/antagonists & inhibitors
- Receptors, Retinoic Acid/metabolism*
- Water Pollutants, Chemical/toxicity
- Zebrafish/embryology*
- PubMed
- 25725299 Full text @ Aquat. Toxicol.
- CTD
- 25725299
Citation
Isales, G.M., Hipszer, R.A., Raftery, T.D., Chen, A., Stapleton, H.M., Volz, D.C. (2015) Triphenyl phosphate-induced developmental toxicity in zebrafish: Potential role of the retinoic acid receptor. Aquatic toxicology (Amsterdam, Netherlands). 161C:221-230.
Abstract
Using zebrafish as a model, we previously reported that developmental exposure to triphenyl phosphate (TPP) - a high-production volume organophosphate-based flame retardant - results in dioxin-like cardiac looping impairments that are independent of the aryl hydrocarbon receptor. Using a pharmacologic approach, the objective of this study was to investigate the potential role of retinoic acid receptor (RAR) - a nuclear receptor that regulates vertebrate heart morphogenesis - in mediating TPP-induced developmental toxicity in zebrafish. We first revealed that static exposure of zebrafish from 5-72h post-fertilization (hpf) to TPP in the presence of non-toxic concentrations of an RAR antagonist (BMS493) significantly enhanced TPP-induced toxicity (relative to TPP alone), even though identical non-toxic BMS493 concentrations mitigated retinoic acid (RA)-induced toxicity. BMS493-mediated enhancement of TPP toxicity was not a result of differential TPP uptake or metabolism, as internal embryonic doses of TPP and diphenyl phosphate (DPP) - a primary TPP metabolite - were not different in the presence or absence of BMS493. Using real-time PCR, we then quantified the relative change in expression of cytochrome P450 26a1 (cyp26a1) - a major target gene for RA-induced RAR activation in zebrafish - and found that RA and TPP exposure resulted in a <5-fold increase and decrease in cyp26a1 expression, respectively, relative to vehicle-exposed embryos. To address whether TPP may interact with human RARs, we then exposed Chinese hamster ovary cells stably transfected with chimeric human RARα-, RARβ-, or RARγ to TPP in the presence of RA, and found that TPP significantly inhibited RA-induced luciferase activity in a concentration-dependent manner. Overall, our findings suggest that zebrafish RARs may be involved in mediating TPP-induced developmental toxicity, a mechanism of action that may have relevance to humans.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping